Amines Schiff base formation

CHC(=0)Me, BuNH2, MeCN, reflux, 24 h 16% change in regioselectivity and preservation from deacylation may perhaps be explained by the possibility for Schiff base formation of the synthon and product, respectively, in the presence of the primary amine] 158 a plausible reason for the formation of mono- instead of di-lV-oxides was advanced.158... 

Figure 1.37 A reducing sugar may modify protein amine groups through Schiff base formation followed by an Amadori rearrangement to give a stable ketoamine product. Glucose is a common in vivo modifier of blood proteins through this process.

Schiff base interactions between aldehydes and amines typically are not stable enough to form irreversible linkages. These bonds may be reduced with sodium cyanoborohydride or a number of other suitable reductants (Chapter 2, Section 5) to form permanent secondary amine bonds. However, proteins crosslinked by glutaraldehyde without reduction nevertheless show stabilities unexplainable by simple Schiff base formation. The stability of such unreduced glutaraldehyde conjugates has been postulated to be due to the vinyl addition mechanism, which doesn t depend on the creation of Schiff bases. 

Aldehydes and ketones can react with primary and secondary amines to form Schiff bases, a dehydration reaction yielding an imine (Reaction 45). However, Schiff base formation is a relatively labile, reversible interaction that is readily cleaved in aqueous solution by hydrolysis. The formation of Schiff bases is enhanced at alkaline pH values, but they are still not stable enough to use for crosslinking applications unless they are reduced by reductive amination (see below). 

Conjugation through Schiff base formation followed by reduction to secondary amine linkage. 

Aldehyde particles are spontaneously reactive with hydrazine or hydrazide derivatives, forming hydrazone linkages upon Schiff base formation. Reactions with amine-containing molecules, such as proteins, can be done through a reductive amination process using sodium cyanoborohydride (Figure 14.21). 

Wash 10 mg of aldehyde particles 3 times with 10 mM sodium phosphate, pH 7.4 (coupling buffer). Buffers of higher pH value (i.e., carbonate buffer at pH 10) will result in more efficient Schiff base formation with amine-containing molecules than neutral pH conditions. 

Proteins may be modified with oxidized dextran polymers under mild conditions using sodium cyanoborohydride as the reducing agent. The reaction proceeds primarily through e-amino groups of lysine located at the surface of the protein molecules. The optimal pH for the reductive amination reaction is an alkaline environment between pH 7 and 10. The rate of reaction is greatest at pH 8-9 (Kobayashi and Ichishima, 1991), reflecting the efficiency of Schiff base formation at this pH. 

Electrophilic site for Schiff base formation with reactive amines such as a-amino acids. Corresponding transaminated species, pyridoxamine, reacts with electrophilic carbonyl compounds... 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

Schiff s base formation occurs by condensation of the free amine base with aldehyde A in EtOAc/MeOff. The free amine base solution of glycine methyl ester in methanol is generated from the corresponding hydrochloride and triethylamine. Table 4 shows the reaction concentration profiles at 20-25°C. The Schiffs base formation is second order with respect to both the aldehyde and glycine ester. The equilibrium constant (ratio k(forward)/ k(reverse)) is calculated to be 67. 

The first step in one synthesis of the antipsychotic dmg clozapine (37-5) involves UUman coupling of anthranUic acid (37-1) with 2,4-dichloronitrobenzene (30-1) to give the substituted anthranilate (37-2). The carboxyl group is then converted to the A-methylpiperazinamide (37-3) via a suitably activated intermediate as, for example, the imidazohde obtained by reaction with carbonyidiimidazole (CDl). The nitro group is then reduced to amine (37-4) by means of catalytic hydrogenation. Intramolecular Schiff base formation catalyzed by toluenesulfonic acid then completes the synthesis of clozapine (37-5) [38]. 

In enzymic decarboxylations the mechanistic pathway seems to involve Schiff base formation between an —NH2 from a lysine residue and a C=0 of the keto acid.52 Likewise, with small-molecule primary amines, catalysis of decarboxylation of /3-ketoacids53-58 has been ascribed to a Schiff base intermediate. The overall reaction for oxalacetate is... 

It became of interest to see if we could obtain any indication of Schiff base formation with the polymer. Since spectroscopic probes would be obscured with the actual substrate, oxalacetate, because of the progress of the decarboxylation reaction (32), we have examined instead the spectra of oxalacetate-4-ethyl ester in solutions of the same modified poly-(ethylenimine) PEIQ—NH2. Such solutions develop a new absorption band at 290 nm. Furthermore, this band is essentially abolished if NaBH4 is added to the solution (Fig. 21). As is well known, NaBH4 reduces Schiff base linkages to amine groups.43-44... 

Naphthalene- and anthracene-derived phenols did, however, almost uniformly precipitate (Table VI). In natural materials (not grapes or wines) which contain them they would be included in the formaldehyde precipitable group. Several primary amines capable of SchifFs base formation reacted with formaldehyde to lose their F-C oxidizability, but only the resorcinol analog, 3-aminophenol, precipitated (Table VIII). Sulfite also reacted but did not precipitate with formaldehyde, and the F-C oxidizability was suppressed (Table IX). The resorcinol derivative, 2,4-dimethoxycinnamic acid, formed a precipitate with formaldehyde, but it did not react appreciably in the F-C assay. 

Decarboxylation of p-oxoacids. Beta-oxoacids such as oxaloacetic acid and acetoacetic acid are unstable, their decarboxylation being catalyzed by amines, metal ions, and other substances. Catalysis by amines depends upon Schiff base formation,232 while metal ions form chelates in which the metal assists in electron withdrawal to form an enolate anion.233 235... 

A good example of how transient chemical modification can activate a substrate is Schiff base formation from the condensation of an amine with a carbonyl compound (equation 2.34). The Schiff base may be protonated at neutral pH. 

Melt poly condensation is also the most popular method for other thermotropic condensation polymers, including the polyazomethines where the reaction between aromatic aldehydes or ketones and primary amines with elimination of water leads to azomethine (Schiffs base) formation 48). 

The reaction occurs rapidly at alkaline pH (7—10), with higher pH values resulting in better yields due to faster Schiff base formation. To ensure complete conversion of available aldehydes to amines, add the ammonia or diamine compound to the reaction in at least a 10-fold molar excess over the expected number of formyl groups present, Diamines that are commonly used for this process include ethylene diamine, diamino-dipropylamine (3,3 -iminobispropylamine), 1,6-diaminohexane, and the Jeffamine derivative EDR-148 containing a hydrophilic, 10-atom chain (Texaco Chemical Co.). 

---